Synthesis of C18 -modified vitamin D compounds and compounds resulting therefrom

ABSTRACT

The invention relates to a new vitamin D compound, substituted in the 18-position with an alkyl group, a hydroxy group, an alkoxy group, an alkenyl group, an alkynyl group, a fluorinated alkyl group or a fluorinated alkenyl group. The invention also relates to a method of preparing said vitamin D compound and to a lactone and a hydrindane intermediate. The vitamin D compound is of the general formula ##STR1##

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a division of U.S. application Ser. No.08/333,305, filed Nov. 1, 1994, now U.S. Pat. No. 5,637,742; which, inturn, is a division of U.S. application Ser. No. 08/180,463, filed Jan.12, 1994, now U.S. Pat. No. 5,403,940; which, in turn, is a continuationof U.S. application Ser. No. 07/907,121, filed Jul. 1, 1992, nowabandoned.

The invention relates to a new vitamin D compound, to a method ofpreparing this compound and to an intermediate that can be used in thismethod.

It is generally known, that vitamin-D compounds or vitamin-D relatedcompounds ("vitamin-D compounds") have a strong biological activity andmay be used in all those cases in which problems with the calciummetabolism play a part. A few years ago it was found that various activevitamin-D compounds also have other pharmacotherapeutic activities andmay be used successfully, for example, for the treatment of certain skinand bone diseases, for cosmetic applications and for treating diseaseswhich are related to cell differentiation, cell proliferation orimbalance in the immune system, including diabetes mellitus,hypertension and inflammatory diseases such as rheumatoid arthritis andasthma. In addition, these compounds may be used in various veterinaryapplications.

It is therefore of the utmost importance to have the disposal of anarsenal of active vitamin-D compounds for said various applicationfields so as to be able to make the best possible choice of vitamin-Dcompounds for the application in view.

Vitamin-D compounds which are of interest for the applications mentionedhereinbefore are hydroxylated vitamin-D compounds, for example,1α-hydroxyvitamin-D₃ or 1α-hydroxycholecalciferol,24R-hydroxy-vitamin-D₃, 1α, 25-dihydroxyvitamin-D₃,25-hydroxyvitamin-D₃,24R,25-dihydroxyvitamin-D₃,1α,24R-dihydroxyvitamin-D₃, 1α,24R,25-trihydroxyvitamin-D₃,1α,25-dihydroxyvitamin-D₃ -26,23-lactone, 25-hydroxyvitamin-D₃-26,23-lactone, 22-oxa-substituted vitamin-D compounds optionally havingelongated C₁₇ -side chains, vitamin-D₂ compounds hydroxylated in the1α-, 24- and/or 25-position(s), and vitamin-D compounds having elongatedC₁₇ -side chains, such as 26-homo compounds, 26,27-dihomo compounds,24,24-dihomo compounds and 24,24,24-trihomo compounds with or withoutdouble bonds and/or hydroxy groups in the side chains, as well asrelated vitamin-D compounds having a triple bond, e.g. a C₂₃ -C₂₄-triple bond, or a C₃ -C₆ cycloalkyl group, e.g. a C₂₄ -cyclopropylgroup, in the C₁₇ -side chain. Furthermore, fluorinated and optionallyhydroxylated vitamin-D compounds are of importance due to theirbiological activities.

From the above enumeration of vitamin D compounds it will be clear thatthe variations in the C₁₇ -side chain of the vitamin D molecule areknown to contribute to a certain selective activity, i.e. the intendedactivity without detrimental side-effects. In general, modified vitaminD compounds are potentially interesting substances, in principlesuitable for the above-defined medical indications. In this connectionthere is a need for well accessible modified vitamin D compounds havinga variety of C₁₇ -side chains. As a matter of fact, both the startingcompounds for the preparation of such vitamin-D compounds must be easilyavailable or accessible, and the multistep preparation process must leadto the intended purpose with sufficient selectivity and efficiency. Inaddition, said purpose is not a specifically defined substance, but avariety of modified vitamin-D compounds, as indicated hereinbefore, fromwhich a selection may be made at will. This means that the preparationprocess should be suitable without fundamental changes for the synthesisof an as large as possible number of different vitamin-D compounds.

It is therefore the objective of the present invention to provide a newclass of vitamin D compounds, which is well accessible from readilyavailable or accessible starting materials.

According to the present invention this objective can be achieved with anew vitamin D compound of the general formula ##STR2## wherein R₁ is ahydrogen atom or a hydroxy group;

R₃ is a C₂ -C₅ alkyl group, a hydroxy(C₁ -C₄)-alkyl group, a C₁ -C₄alkoxymethyl group, a C₂ -C₅ alkenyl group, a C₂ -C₅ alkynyl group, afluorinated C₂ -C₅ alkyl group or a fluorinated C₂ -C₅ alkenyl group;

R₄ is a hydrogen atom or a C₁ -C₄ alkyl group;

R₅ is a branched or non-branched, saturated or unsaturated aliphatichydrocarbyl or hydrocarbyloxy group, which comprises 1 to 16 carbonatoms and which is optionally substituted with one or more substituents,selected from hydroxy groups, ether groups, oxo functions, cyclopropylgroups, lactone groups and fluorine atoms;

R₆ is a hydrogen atom or a C₁ -C₄ alkyl group; and

A and B are each individually hydrogen atoms or methyl groups, or

A and B form together a methylene group.

Examples of suitable substituents R₃ are:

C₂ H₅, CH₂ OH, CH═CF₂, CH₂ CHF₂, CH═CH₂ and C.tbd.CH.

A hydroxy group in the vitamin D compound of the above formula I may beprotected by a reaction with a suitable esterification or etherificationagent. A suitable esterification agent is an alkylchlorocarbonate having2 to 5 carbon atoms, or an aromatic carboxylic acid, a saturatedaliphatic carboxylic acid having 1 to 4 carbon atoms, p-toluenesulphonicacid, methanesulphonic acid, trifluoroacetic acid or a derivative ofthese acids suitable for the esterification reaction. In order toprotect hydroxy groups in the form of an ether, in principle anyetherification agent known for this purpose is suitable: for example, atriphenylmethylhalide, 2,3-dihydropyrane, a trialkylsilylhalide, adiphenylalkylsilylhalide, an alkoxyalkylhalide, atrialkylsilylethoxymethylhalide, or a derivative thereof, the alkylgroups of which have 1 to 6 carbon atoms.

Particularly suitable for this purpose are trimethylsilylchloride,tert.-butyldimethylsilylchloride,dimethyl-(1,1,2-trimethylpropyl)silylchloride,trimethylsilyl-ethoxymethylchloride, methoxymethylchloride,methoxyethylchloride, tert.-butyldimethylsilyl trifluoroacetate, ortrimethylsilylimidazole, because these etherification agents readilyreact with the hydroxy group to be protected to form an ether function,which on the one hand is sufficiently stable under the conditions of thereaction or reactions in view, but on the other hand can easily beremoved [deprotection) to recover the original hydroxy group;tert.-butyldimethylsilylchloride is to be preferred, because thetert.-butyldimethylsilyl group has been found to be excellently suitableas a protective group.

The above new vitamin D compounds of the invention, presented by thegeneral formula I, are valuable substances. The biological results, asillustrated in the Examples, indicate that these compounds are promisingas biologically active substances and may be used in all above-mentionedpharmacotherapeutic indications, more in particular for the treatment ofosteoporosis, renal osteodystrophy, osteomalacia, skin disorders such aspsoriasis, eczema and dermatitis, myopathy, leukemia, breast and coloncancer, osteosarcomas, cutaneous squamous cell carcinomas, certainimmunological disorders, and transplant rejections. Furthermore, the newvitamin D compounds of the invention may be used for wound healing andmay be incorporated in cosmetic compositions, such as creams, lotions,ointments and the like, in order to preserve, condition and/or protectthe skin and to improve various skin conditions, such as wrinkles, dryskin, skin slackness and insufficient sebum secretion.

A vitamin D compound is preferred, having the above general formula I,

wherein

R₁, R₃, A and B have the above meanings,

R₄ is a methyl group, and

R is a hydrogen atom or a methyl group, and

R₅ is an aliphatic hydrocarbyl group selected from the group consistingof 3,4-dimethylpenten-1-yl, 3,4-dimethyl-4-hydroxypenten-1-yl,3-hydroxy-4-methylpentyl,4-hydroxy-4-methylpentyl,3,4-dihydroxy-4-methylpentyl,3,3-difluoro-4-hydroxy-4-methylpentyl,3-methylbutoxy, 3-hydroxy-3-methylbutoxy,3-cyclopropyl-3-hydroxypropen-1-yl and3-cyclopropyl-3-hydroxy-3-methylpropen-1-yl; or its corresponding24-homo-, 26-homo-, 24,24-dihomo-, 26,27-dihomo-, 24,26,27-trihomo- or24,24,26,27-tetrahomo-vitamin D analogue.

It is a special merit of the present invention that the above newvitamin D compound of the invention can easily be prepared from readilyavailable starting materials. In particular, it has been found, that themodification at C₁₈ can easily be achieved by using a suitablemethyl-substituted compound, e.g. a 7a-methylhydrindan-4-ol compound, asthe starting material. Consequently, the present invention also relatesto a method of preparing the vitamin D compound as defined above, whichmethod is characterized in that a hydrindane compound of the generalformula ##STR3## wherein R₇ is a branched or non-branched, saturated orunsaturated aliphatic hydrocarbyl group, which comprises 1 to 16 carbonatoms and which is optionally substituted with one or more substituentsselected from protected hydroxy groups, ether groups, protected oxofunctions, C₁ -C₄ alkyl ester groups, cyclopropyl groups, and fluorineatoms;

is oxidized to a lactone intermediate of the general formula ##STR4##wherein R₇ has the above meaning, after which said lactone intermediateis reduced and then subjected, if desired, to a reaction sequence tointroduce substituent R₃ and to convert substituent R₇ in a manner knownper se for related compounds into substituent R₄ C(R₅) R₆ ;

after which the hydrindane compound obtained, having the general formula##STR5## is oxidized to the corresponding hydrindane-4-one compound andis then reacted, in a manner known per se for related compounds, either(a) with a Wittig reagent of the general formula ##STR6## wherein R₁ 'is a hydrogen atom or a protected hydroxy group,

R₂ is a protected hydroxy group, and

A and B have the above meanings, or (b), after enolization, with anenyne compound of the general formula ##STR7## wherein R₁ ' and R₂ havethe above meanings, followed by hydrogenation and equilibration; theproduct obtained, if desired, being deprotected.

It is an additional merit of the present invention, that the startinghydrindane compound of the above formula II can easily and simply beprepared from a readily available seco steroid as a starting material,and that therefore certain vitamin D compounds are better accessible byusing this compound as a synthon. Said hydrindane compound can beprepared in a simple manner by subjecting a seco steroid of the generalformula ##STR8## wherein R₇ has the above meaning, and

Z is a hydroxymethylene group, a carbonyl group or a ketalised carbonylgroup,

or a hydroxy-protected derivative thereof as defined above, to anoxidative cleavage of the C₇ -C₈ double bond, after which thehydrindan-4-one product obtained is converted with a suitable reductant,a compound of the above general formula II being formed.

The above oxidative cleavage can be performed by ozonolysis in aconventional manner, viz. by addition of ozone, followed by a reductivecleavage of the formed ozonide. Alternatively, said oxidative cleavagecan be carried out by an oxidation reaction with the aid of a suitableoxidant, preferably with potassium permanganate, followed by a treatmentwith lead tetraacetate and by reduction.

Particularly suitable as a starting material for the above preparationmethod is a seco steroid of the above general formula XIII, wherein bothR₇ and Z are ketalized acetyl and carbonyl groups, respectively, becausesuch a compound can simply be prepared by irradiating the readilyavailable 9,10-secopregna-5,7,10(19)-triene-3,20-diketal.

Equally suitable as starting materials are vitamin D₂ compounds, i.e. acompound of the above general formula XIII, wherein Z is ahydroxymethylene group and R₇ is a 1,4,5-trimethylhexen-2-yl group.Examples are presented in Scheme A.

It will be self-evident, that Scheme A, as well as the other Schemesattached, only serves to illustrate the invention. Various modificationsand variations are feasible within the framework of the presentinvention.

In the attached Schemes the following abbreviations are used:

TBS=t.butyldimethylsilyl;

LDA=lithium diisopropyl amide;

Me=methyl;

X=halogen;

φ=phenyl;

mCPBA=m-chloroperbenzoic acid;

sBu=sec.butyl;

Ts=toluenesulphonyl (tosyl);

Ac=acetyl;

TMS=trimethylsilyl;

Et=ethyl;

Pr=n-propyl;

Tf=trifluoromethylsulphonyl;

tBu=tert.butyl;

Py=pyridine;

DIBAL-H=diisobutylaluminium hydride; and

THF=tetrahydrofuran.

Reaction conditions Scheme A; (1)→a(2) and (3)→(4):

Addition of ozone at decreased temp. in dichloromethane, methanol,ethanol, etc., in presence of pyridine, followed by reduction of ozonideby LiAlH₄, NaBH₄, DIBAL-H or other complex metal hydrides.

Alternative I: oxidation by KMnO₄ in H₂ O/EtOH at decreased temp.,oxidative cleavage by Pb(OAc)₄ and reduction.

Alternative II: epoxidation by mCPBA in dichloromethane at decreasedtemp., followed by oxidative cleavage.

Hydrindane compounds obtainable from the particularly suitable secosteroid, as defined above, are new. Therefore the present invention alsorelates to a hydrindane compound of the general formula ##STR9## whereinR₇ " is a ketalized acetyl group, preferably a 1,1-dimethoxyethyl group,a 1,1-diethoxyethyl group or a 2-methyl-1,3-dioxacyclopent-2-yl group.

The resulting hydrindane compound of the general formula II is asuitable starting substance for the synthesis of new vitamin D compoundsin that this substance easily allows modification of the C_(7a) -methylgroup through the lactone intermediate of the general formula III asdefined above. Said lactone intermediate can easily be produced from theabove hydrindane compound by an oxidation reaction, preferably in twoseparate oxidation steps. In the first oxidation step an oxidant is usedwhich is preferably selected from lead tetraacetate and phenyliodosodiacetate, and subsequently with silver acetate, to obtain thetetrahydrofuran intermediate, having the general formula ##STR10##wherein R₇ has the above meaning. In the second oxidation step anoxidant is used which is preferably selected from ruthenium oxide,chromium trioxide, benzyl triethylammonium permanganate andtrichloroisocyanuric acid, to obtain the lactone intermediate of thegeneral formula III above. Examples are also presented in Scheme A.

As a particular aspect of the present invention it has been found, thatby using ruthenium oxide as the oxidant in said second oxidation step, aterminal isopropyl group in the hydrindane molecule can be oxidized tothe corresponding 2-hydroxyprop-2-yl group, simultaneously with thelactone formation. In this manner, for instance 25-hydroxyvitamin Dcompounds can be synthetized very easily. Reaction conditions Scheme A;(2)→(6),(4)→(9) and (4)→(13):

reaction (2)→(5): Pb(OAc)₄ in benzene at reflex temp.

reaction (5)→(6): oxidation with RuO₂ in presence of NaIO₄ in mixture ofCH₃ CN/H₂ O/CCl₄ at room temp.

reaction (4)→(7): acetylation with Ac₂ O in Py at approx. 0° C. reaction(7)→(8): see (2)→(5).

reaction (8)→(9): see (5)→(6). reaction (4)→(10): iodination with I₂/P(Ph)₃ in presence of imidazole in THF at approx. 0° C.

reaction (10)→(11): reaction with methylacrylate in presence of Zn/ICuunder sonication in EtOH/H₂ O.

reaction (11)→(12): see (2)→(5).

reaction (12)→(13): reaction with MeLi in THF at approx. 0° C., followedby oxidation as in (5)→(6).

It will be clear from Scheme A, that the C₁₈ -modification of thevitamin D molecule can be performed at different stages of the C₁₇ -sidechain build-up procedure.

The lactone intermediate of the general formula III is new. Thereforethe present invention also relates to said lactone intermediate, whichcan be prepared as described above.

Said lactone intermediate is to be considered as a versatileintermediate, permitting interesting modifications of the molecule andfinally resulting in C₁₈ -modified vitamin D compounds. To obtain ahydroxymethyl group at C₁₃ of the final vitamin D molecule, said lactoneintermediate can first be reduced with a suitable reducing agent, e.g.with LiAlH₄. This reaction is presented in Scheme B, wherein R₁₀encompasses the substituents shown in compounds (6) and (13) of SchemeA. The hydroxymethyl group can be converted, if desired, to thecorresponding C₁ -₄ alkylether by any conventional etherificationreaction. With a different reducing agent, preferably DIBAL-H, thereduction reaction results in a reduction of the lactone function to thelactol function, which intermediate is suitable for reacting with aWittig reagent: Scheme B. The product obtained by the last reaction canbe converted, if desired, as indicated in Scheme B.

Reaction conditions Scheme B: (14)→(15) and (14)→(16) etc.:

reaction (14)→(15): LiAlH₄ in THF at approx. 0° C.

reaction (14)→(16): DIBAL-H in toluene at decreased temp. reaction(16)→(17): φPCH₃ Br in THF in presence of tBuOK at room temp.

reactions (16)→(21) and (16)→(19): corresp.

reactions (17)→(18) and (21)→(22): catalytic hydrogenation in suitablesolvent.

reaction (19)→(20): under influence of BuLi in THF at decreased temp.

The product thus obtained is a suitable synthon for the preparation ofC₁₈ -modified vitamin D compounds having a variety of C₁₇ -side chains.

In an equally attractive manner the new vitamin D compounds of thepresent invention can be prepared starting from a hydrindane compound ofthe general formula ##STR11## wherein

R₇ has the above meaning, and

R₈ is a hydroxy-protecting group, as defined above.

It has been found that said hydrindane compound can easily be oxidizedto a lactone intermediate of the general formula ##STR12## wherein thesymbols have the above meanings.

This lactone intermediate is also a versatile intermediate for thesynthesis of various vitamin D compounds and is completely comparablewith the lactone intermediate of formula III, described above.Modification of the 7a-methyl group of the hydrindane structure, asdescribed for lactone intermediate III, can be performed in the samemanner starting from the above intermediate VIII, ultimately producingthe desired C₁₈ -modified vitamin D compound. Both the synthesis oflactone intermediate VIII and the conversion of this intermediate intoC₁₈ -modified vitamin D compound proceed under the same conditions asdescribed above for lactone intermediate III.

It will be understood, that the invention also relates to the lactoneintermediate of the general formula VIII per se.

Alternatively, for the synthesis of C₁₈ -modified vitamin D compounds, ahydrindane compound of the general formula ##STR13## wherein R₆ has theabove meaning, can be used as a starting material. This compound isfirst converted to the corresponding cyano-hydrin of the general formula##STR14## after which this intermediate is converted to a hydrindaneintermediate of the general formula ##STR15## by Pb(OAc)₄ in thepresence of I₂ and under the influence of heat and light. The cyanogroup can then be converted in a manner known per se to producesubstituent R₃ in the 7a-position of the hydrindane structure. Build-upof the desired C₁₇ -side chain of the vitamin D molecule andintroduction of the A-ring system can be performed as described below.

The desired C₁₇ -side chain can be built up in a manner known per se forrelated compounds, e.g. as described by Baggiolini et al. inJ.Am.Chem.Soc. 104, 1982, 2945-2948, and by Wicha et al. in J.C.S.PerkinI, 1978, 1282-1288, and in J.C.S.Chem. Comm., 1975, 968-969. After saidside chain formation, in which group R₄ C(R₅)R6 is substituted for R₇, ahydrindane compound is obtained, having the general formula ##STR16##wherein the symbols have the meanings defined above.

After said C₁₇ -side chain formation, the A-ring system of the vitamin-Dcompound can be introduced by first converting the hydroxy group to aketo group via oxidation, and by then converting the keto compound thusobtained with a Wittig reagent of the general formula ##STR17## wherein

R₁ ' is a hydrogen atom or a protected hydroxy group,

R₂ is a protected hydroxy group, and

A and B have the above meanings, the product obtained, if desired, beingdeprotected. This A-ring introduction is described in an article byWovkulich et al.: Tetrahedron 40, 1984, 2283-2296.

Alternatively, the A-ring can be introduced by converting said ketocompound, after enolization, with an enyne compound of the generalformula ##STR18## wherein the symbols have the above meanings, followedby hydrogenation and equilibration.

The product obtained can equally be deprotected. This latter A-ringintroduction, visualized in Scheme E, is described by Lythgoe et al inJ.Chem.Soc.(C), 1971, 2960-2966, and in J. C. S. Perkin I, 1974,2654-2657, and by Mourino et al. in Tetrahedron Letters 29, 1988,1203-1206.

After the above reactions have been performed, the synthesis of thedesired vitamin-D compound has been completed.

In Scheme C an example of the preparation of vitamin D compoundsaccording to the above synthetic pathway is presented. Substituent R₃ isdefined above, as well as A and B. A and B preferably form together amethylene group or both represent hydrogen atoms.

Reaction conditions Scheme C

Reaction (23)→(24): alkaline saponification in an alcohol; followed byiodination with I₂ in presence of PPh₃ and imidazole, in THF as solvent.

Reaction (24)→(25): reaction with methacrylate under sonication inpresence of Zn and CuI.

Reaction (25)→(26): reaction with MeMgBr in THF at approx. 0° C.

Reaction (26)→(27) proceeds in two reaction steps: oxidation, e.g. witha Cr-containing oxidant; and reaction with trimethylsilylimidazole toprotect free OH.

Reaction (27)→(28) proceeds via a Wittig reaction under conventionalWittig conditions and a deprotection (see above).

The desired C₁₇ -side chain can also be built up in a different mannerknown per se for related compounds, e.g. as described by Kyler et al. inJ.Am.Chem.Soc. 105, 1983, 619-621, and in J.Org.Chem. 49, 1984,1084-1090, by Narwid et al. in Helv.Chim.Acta 57, (Fasc. 3), 1974,771-781. After the Cu₇ -side chain formation, the A-ring system of thevitamin-D compound can be introduced as described above.

Scheme D illustrates the above synthetic reactions.

Reaction conditions Scheme D

Reaction (29)→(30) proceeds via the following reaction steps: Metalationof the substituted propene using sBuLi (10% HMPA-THF; decreased temp.)and condensation with compound (29); conversion with sBuLi (10%HMPA-THF, decreased temp.) and reaction with pentanone-3; reaction withNiCl₂ in aqueous tBuOH; Raney nickel reduction finally leads to compound(30).

Reaction (29)→(31) proceeds via the following reaction steps: Grignardreaction with vinylmagnesiumchloride in THF; reaction with diketene indecaline in the presence of s-collidine; cat. hydrogenation (H₂ /PtO);and finally Grignard reaction with methylmagnesiumbromide indiethylether.

Reaction (30,31)→(32,38): see Reaction Scheme C.

In another, equally interesting chain-extending reaction, the carbonylgroup of the starting hydrindane compound is first reduced, e.g. withsodium borohydride, or is first converted in a Grignard reaction with amethylmagnesium halogenide, to the corresponding hydroxy compound.O-alkylation of this hydroxy compound, followed by the above-describedintroduction of the A-ring system, results in 22-oxa-substitutedvitamin-D compounds. The above O-alkylation can be performed in a mannerknown per se for related compounds, e.g. as described in the recentlypublished international patent applications Wo 90/09991 and WO 90/09992.

Scheme E is an illustration of the above synthetic reactions.

Reaction conditions Scheme E

Reaction (29)→(33): Reduction with LiAlH₄ or NaBH₄.

Reaction (29)→(34): Grignard reaction with MeMgI under conventionalGrignard conditions.

Reaction (33,34)→(35,36) proceeds via the following reaction steps:Deprotonation with NaH in THF, followed by reaction withω-bromoalkylether; desilylation with tetrabutylammonium fluoride in THF,followed by oxidation with a Cr-containing oxidant; Wittig reactionunder conventional Wittig conditions, followed by deprotection.

Reaction (33,34)→(35,36) proceeds alternatively via the followingreaction steps: Deprotonation followed by reaction withω-bromoalkylether (see above); desilylation followed by oxidation (seeabove); reaction with LDA, followed by reaction with phenyltrifluoromethylsulfonimide; reaction with enyne under influence of aPd-cat. and Et₃ N in DMF (increased temp.); finally catalyticalhydrogenation (H₂ /Pd-BaSO₄), heating and deprotection (see above). Thevitamin-D compounds prepared as described above can occur in differentdiastereoisomeric configurations. The present invention includes thepreparation of such diastereoisomers in pure form and of mixtures ofsuch stereoisomers. In addition, product (35), as prepared aboveaccording to Scheme E, can occur in two different stereochemicalconfigurations at C-20, viz. the R- and the S-configuration.

The invention will now be described in greater detail with respect tothe following specific examples.

A survey of the reaction equations, illustrated in the Examples, isshown in the Reaction Schemes attached, in particular in Schemes F andfollowing. The compound numbers correspond, if possible, to the numbersused in Schemes A and B. The reaction steps described in the Examplesare indicated with the numbers of starting compound and product,corresponding with those used in the Schemes. In the spectral data thenumbering corresponds to the well-known numbering of the C-atoms in thevitamin D molecule.

EXAMPLE I

Reaction (3)→(4):

Vitamin D₂ (8.00 g, compound 3) is dissolved in 700 ml methanol and 7 mlpyridine. After flushing with N₂ for 30 minutes, ozone is passed throughthe solution, cooled to -80° C., during 2.5 hours. The resulting ozonideis directly reduced by adding 2 g NaBH₄ to the reaction mixture,followed by stirring for 20 minutes at -80° C. Addition of anotherportion of NaBH₄ (1 g), after 30 min. at room temperature and againanother 1 g portion of NaBH₄ after standing overnight at roomtemperature. The reaction mixture is concentrated and continuouslyextracted with diethylether for 24 hours. The organic layer is dried,filtered, and evaporated to dryness. The residue is chromatographed oversilicagel (eluent 25% EtOAc/petroleum ether), yielding 5.71 g of product(4). Rf (30% EtOAc/petroleum ether) 0.10; m.p. 110° C.

¹ H-NMR (CDCl₃, δ): 0.94 (s, 3H, CH₃ -18), 1.01 (d, J=6.6 Hz, 3H, CH₃-21), 3.37 (dd, J=10.5, 6.7 Hz, 1H, H-22), 3.62 (dd, J=10.5, 3.5 Hz, 1H,H-22), 4.07 (9, 1H, H-8).

EXAMPLE II

Reaction (4)→(10)

A solution of 1.056 g of compound (4), 1.430 g PPh₃ and 1.016 gimidazole in 25 ml dry THF under argon is cooled in an ice-water bath.Iodine (1.391 g) is added and the temperature is maintained at approx.0° C. for 15 min. After allowing the reaction mixture to reach roomtemperature, THF is evaporated, satd. NaHCO₃ is added and the reactionmixture is extracted twice with diethylether. The organic phase isseparated, washed with 5% Na₂ SO₃ solution, dried, filtered,concentrated under reduced pressure and finally filtered over silica gel(eluent: 25% EtOAc/hexane). The desired product is obtained as a viscousliquid in a yield of 1.533 g.

¹ H-NMR (CDCl₃, δ):0.98(s, 3H, CH₃ -18), 1.01 (d, J=5.40 Hz, 3H, CH₃-21), 3.19 (dd, J=4.60, 9.61 Hz, 1H, CHHI), 3.27 (dd, J=7.39, 9.54 Hz,1H, CHHI), 4.10 (a, 1H, H-8).

¹³ C-NMR (CDCl₃, δ): 14.28, 17.28, 20.57, 21.07, 22.30, 26.45, 33.50,36.30, 40.05, 41.78, 52.28, 55.87, 69.15.

EM [70 eV, m/z (%)]: 322 (M⁺, 0.3), 307 (16.5), 177 (99.6), 135 (50.7),111 (100).

EXAMPLE III

Reaction (10)→(11)

Zn (1.785 g) and 2.229 g purified CuI are introduced under argon into 3ml oxygen-free EtOH/H₂ O. This reaction mixture is sonicated under argonfor 10 min. To this mixture is added dropwise a solution of 1.264 g ofcompound (10) in 6 ml (66.7 mmoles) freshly distilled methylacrylate atroom temperature under argon and while sonicating. Sonication iscontinued for 30 minutes. After addition of 10 ml NH₄ Cl, the reactionmixture is again sonicated for 10 minutes. Filtration over celite,washing with diethylether, washing of the diethylether phase withsaturated NaCl solution and drying produces a solution in ether, which,after evaporation to dryness, yields a residue. This residue is purifiedby column chromatography (silica; eluent: 5-20% EtOAc/hexane), affordingthe desired product (11) in a yield of 615 mg.

EXAMPLE IV

Reaction (11)→(12):

Under protection against light, 7.210 g of Pb(OAc)₄ is added to acooled, stirred solution of compound (11) (1.994 g) in 275 ml drybenzene under argon. After 20 hours reflux a second portion of 940 mg ofPb(OAc)₄ is added, and the reaction mixture is refluxed for another 10hours. After addition of saturated NaCl solution, the mixture isextracted with EtOAc and the organic phase is dried, filtered andconcentrated under reduced pressure. The residue is purified by columnchromatography (eluent: 5%-20% EtOAc/hexane), yielding 1.22 g of thedesired product (12). ¹ H-NMR (CDCl₃ δ): 0.90 (d, J=6.71 Hz, 3H, CH₃-21), 3.66 (s, 3H, COOCH₃), 3.68 (d, J=8.14 Hz, 1 H, CHHO), 3.74 (d,J=8.20 Hz, 1H, CHhO), 4.13 (d, J=4.33 Hz, 1H, H-8). ¹³ C-NMR (CDCl₃,δ):19.04, 19.04, 21.76, 25.11, 29.18, 32.56, 34.23, 35.64, 37.49, 37.49,51.30, 51.72, 54.28, 58.14, 70.93, 79.03, 174.12.

EXAMPLE V

Reaction (37)→(11):

NaBH₄ (1.088 g) is added in small portions to a cooled (0° C.) andstirred solution of 2.014 g of compound (37) in 25 ml of dry methanol.After 30 minutes the solvent is evaporated. The residue is dissolved indiethylether, washed with water, dried and filtered. Columnchromatography (eluent: 10% EtOAc/hexane) yields 1.663 g of product(11), identical with the product of Example III.

EXAMPLE VI

Reaction (12)→(12A):

MeLi (17.985 moles) is added to a solution of 2.289 g (8.175 mmoles) ofcompound (12) in 125 ml dry diethylether, cooled at -80° C., under argonwhile stirring. At room temperature 5 ml water is added and the reactionmixture is extracted with diethylether, washed with satd. NaCl solution,dried and filtered. Flash column chromatography (eluent: 10-25%EtOAc/hexane) yields 2.050 g of product (12A).

¹ H-NMR (CDCl₃, δ): 0.89 (d, J=6.60 Hz, 3H, CH₃ -21), 1.20 (s, 6H, CH₃-26,27), 3.70 (d, J=8.18 Hz, 1H, CHHO), 3.72 (d, J=8.22 Hz, 1H, CHHO),4.13 (d, J=4.33 Hz, 1H, H-8).

¹³ C-NMR (CDCl₃,): 19,08, 19.18, 21.12, 25.17, 29.14, 29.26, 29.30,32.61, 36.76, 37.55, 37.78, 44.22, 52.02, 54.34, 58.20, 70.95, 71.03,79.09.

EXAMPLE VII

Reaction (12A)→(13):

NaIO₄ is added to a solution of 267 mg of compound (12A) in a mixture ofCCl₄ /H₂ O/CH₃ CN (4:8:4 ml). After vigorous stirring for one minuteRuO₂.H₂ O is added. After vigorous stirring for 17 days, 25 ml water isadded and the reaction mixture is extracted with CH₂ Cl₂ (3×25 ml).Drying of the organic phase, filtration and concentration yields aresidue, which is purified over a silica gel column (eluent: 5%-15%EtOAc/hexane). The desired product (13) is obtained in a yield of 157mg. ¹ H-NMR (CDCl₃,δ): 1.10 (d, J=6.53 Hz, 3H, CH₃ -21), 1.21 (s, 6H,CH₁₃ -26,27), 4.56 (d, J=4.55 Hz, 1H, H-8).

EXAMPLE VIII

Reaction (13)→(14):

Chloromethoxymethane (0.160 ml, 2.163 mmoles), diisopropyl-ethylamine(0.378 ml, 2.163 mmoles) and 4-dimethylaminopyridine (17 mg, 0.139mmoles) are added to a stirred, cooled (0° C.) solution of 145 mg ofcompound (13) in 8 ml dry CH₂ Cl₂ under argon. After stirring for 18hours, water (10 ml) is added and the reaction mixture is extracted withCH₂ Cl₂. The organic phase is washed with 10% hydrochloric acid and withsaturated NaCl solution. After filtration through a silica gel column(eluent: 15% EtOAc/hexane), 163 mg of the desired product (14) isobtained.

¹ H-NMR (CDCl₃, δ): 1.10 (d, J=6.32 Hz, 3H, CH₃ -21), 1.21 (s, 6H, CH₃-26,27), 3.37 (s, 3H, OCH₃), 4.56 (d, J=3.73 Hz, 1H, H-8), 4.71 (5, 2H,OCH₂ O)

EXAMPLE IX

Reaction (14)→(16):

A 1M solution of DIBAL-H in hexane (0.541 mmoles) is added dropwise to acooled (-80° C.) and stirred solution of 135 mg of compound (14) in 2.5ml of dry toluene under argon. After stirring for 2 hours, a solution ofisopropanol in toluene is added. The reaction mixture is allowed toreach room temperature, after which water is added and the emulsion isfiltered over celite. The organic phase is washed with saturated NaClsolution, dried, filtered, concentrated under reduced pressure andchromatographed over silica gel (eluent: 15-25% EtOAc/hexane, yielding101 mg of the desired product (16).

EXAMPLE X

Reaction (16)→(17):

In an argon atmosphere tBuOK (124 mg) and 395 mg MeP⁺ Ph₃ Br- aredissolved in 5 ml dry THF. After reflux for 20 hours, 2.765 ml of thissolution is added via a syringe to a stirred solution of compound (16)(75 mg) in 4 ml dry THF, equally under argon. Reflux for 12 hours,evaporation of the THF, dissolution in 10 ml EtOAc and extraction(twice) with water. The organic phase is washed with saturated NaClsolution, dried, filtered and concentrated. The residue is purified bycolumn chromatography over silica gel (eluent: 15% EtOAc/hexane),yielding 60 mg of the desired product (17).

¹ H-NMR (CDCl₃,δ): 0.83 (d, J=6.7 Hz, 3H, CH₃ -21), 1.21 (s, 6H, CH₃-26,27), 3.37 (8, 3H, OCH₃), 3.95 (s, 1H, H-8), 4.71 (s, 2H, OCH₂ O),5.27 (m, 2H, CH₂ ═), 6.00 (dd, J=9.6, 18.6 Hz, 1H, CH═).

¹³ C-NMR (CDCl₃,δ): 17.04, 17.75, 20.38, 22.26, 26.25, 26.34, 27.13,33.65, 35.26, 35.83, 36.06, 42.24, 48.39, 54.83, 55.04, 57.09, 69.91,76.32, 91.01, 114.43, 138.20.

EXAMPLE XI

Reaction (4)→(7):

Freshly distilled Ac₂ O is added dropwise to a cooled (0° C.) stirredsolution of compound (4) (1.435 g) in 9 ml of dry pyridine under argon.After 12 hours at approx. 0° C., ice and NaHCO₃ are added and thereaction mixture is extracted with diethylether. The organic phase iswashed with 10% hydrochloric acid, saturated NaHCO₃ solution, CuSO₄solution, saturated NaCl solution, dried, filtered and concentrated. Theresidue is crystallized from diethylether/hexane, yielding 1.495 g ofthe desired product (7).

¹ H-NMR (CDCl₃,δ): 0.96 (s, 3H, CH₃ -18), 1.00 (d, J=6.61 Hz, 3H, CH₃-21), 2.05 (s, 3H, CH₃ COO), 3.78 (dd, J=7.44, 10.68 Hz, 1H, H-22), 4.10(dd, J=3.44, 9.8 Hz, 1H, H-22), 4.10 (s, 1H, H-8). ¹³ (CDCl₃, δ): 13.51,16.97, 17.36, 20.92, 22.55, 26.60, 33.60, 35.34, 40.24, 41.97, 52.36,53.33, 69.20, 69.44.

EXAMPLE XII

Reaction (7)→(8):

In a corresponding manner as described in Example IV the above reactionis performed, producing the desired product (8) in a yield of 67%. Rf(25% EtOAc/hexane) 0.6.

¹ H-NMR (CDCl₃, δ): 0.99 (d, J=6.48 Hz, 3H, CH₃ -21), 2.05 (s, 3H, CH₃acetate), 3.68 (d, J=8.18 Hz, 1H, CHHO), 3.74 (d, J=8.19 Hz, 1H,CHHOAc), 3.81 (dd, J=7.4, 10.84 Hz, 1H, CHHOAc), 4.16 (d, J=4.25 Hz, 1H,H-8).

EM (70 eV, m/z(%)]: 252 (M⁺, 5.9), 192 (28.6), 177 (24.0), 149 (28.0),124 (36.9), 111 (100), 96 (35.9), 81 (57.0).

EXAMPLE XIII

Reaction (8)→(9,14A):

In a corresponding manner as described in Example VII the above reactionis performed, producing the desired product in a yield of 76%. ¹ H-NMR(CDCl₃,δ): 1.18 (d, J=6.66 Hz, 3H, CH₃ -21), 2.05 (s, 3H, CH₃ COO), 3.89(dd, J=6.28, 10.84 Hz, 1H, CHHOAC), 4.06 (dd, J=3.51, 10.84 Hz, 1H,CHHOAC), 4.58 (d, J=4.7 Hz, 1H, H-8). EM [70 eV, m/z(%)]: 266 (M⁺, 0.1),223 (20.6), 206 (87.8), 161 (62.4), 147 (95.4), 121 (100), 105 (30.6),91 (52.8), 79 (67.3).

EXAMPLE XIV

Reaction (9,14A)→(16A):

In a corresponding manner as described in Example IX the above reactionis performed, producing the desired product (16A) in a yield of 84%. Rf(60% EtOAc/hexane) 0.3.

EXAMPLE XV

Reaction (16A)→(17A):

In a corresponding manner as described in Example X the above reactionis performed, resulting in the desired product (17A). ¹ H-NMR (CDCl₃,δ):0.95 (d, J=6.11 Hz, 3H, CH₃ -21), 3.40 (dd, J=5.72, 10,47 Hz, 1H,CHHOH), 3.59 (dd, J=2.62, 10.56 Hz, 1H, CHHOH), 3.96 (s, 1H, H-8), 5.29(m, 2H, CH═), 6.00 (dd, J=10.76, 16.82 Hz, 1H, CH═).

EXAMPLE XVI

Reaction (17A)→(18A):

Compound (17A) is hydrogenated at room temperature in methanol under theinfluence of Pd-C. Iodination, as described in Example II, yields thedesired product (18A).

EXAMPLE XVII

Reaction (18A)→(18B):

In a corresponding manner as described in Example III the above reactionis performed, resulting in the desired product (18B).

EXAMPLE XVIII

Reaction (14)→(46) as shown in Scheme H.

The reaction steps described in this Example are indicated with thenumbers of the compounds as used in Scheme H. (a) Reduction of thelactone functionality of compound (14) with diisobutylaluminium hydride(DIBAL-H) affords the 18-hydroxylated compound (38): THF/toluene(1.5:1), -78° C., DIBAL-H (3.5 equiv.), 15 min; -78° C.→room temp.,yield 99%.

¹ H-NMR (CDCl₃,δ): 0.95 (d, J=6.11 Hz, 3-H, CH₃ -21), 1.21 (s, 6H, CH₃-26,27), 3.36 (s, 3H, CH₃ O), 3.64 (d, J=11.8 Hz, 1H, CHHOH), 3.72 (d,J=11.9 Hz, 1H, CHHOH), 4.11 (s, 1H, H-8), 4.70 (s, 2H, OCH₂ O). ¹³ C-NMR(CDCl₃,δ): 18.50, 19.22, 20.27, 22.67,26.24, 26.33, 27.67, 33.78, 35.28,36.37, 38.31, 42.22, 45.84, 52.96, 55.02, 57.33, 62.80, 68.08, 77.51,90.99.

(b) Selective protection of the C-18 hydroxy group of cpd.(38) withtert-butyldimethylsilyl chloride gives cpd.(39): DMF, TBSCI (1.1equiv.), imidazole (1.8 equiv.), cpd.(38) in CH₂ Cl₂, room temp., 1 h,yield 76%.

¹ H-NMR (CDCl₃,δ): 0.12 (s, 6H, CH₃ Si), 0.93 (s, 9H, Me₃ CSi), 0.95 (d,J=4.77 Hz, 3H, CH₃ -21), 1.21 (s, 6H, CH₃ -26,27), 3.36 (s, 3H, OCH₃),3.63 (d, J=10.8 Hz, 1H, CHHOTBS), 3.71 (d, J=11.01 Hz, 1H, CHNOTBS),3.90 (s, 1H, H-8), 4.70 (s, 2H, OCH₂ O).

¹³ C-NMR (CDCl₃, δ): -5.86, -5.74, 18.21, 18.68, 18.92, 20.28, 22.69,25.87, 26.28, 26.34, 27.68, 34.08, 35.44, 36.40, 38.17, 42.27, 45.82,53.41, 55.03, 57.45, 63,75, 67.73, 76.30, 91.02.

(c) Oxidation of silylether (39) with pyridinium dichromate (PDC) givesketone (40): CH₂ Cl₂, 0° C., PDC (2.7 equiv.), PPTS (pyridiniump-toluene sulphonate; trace), 1 h; room temp., 4 h, yield 87%.

¹ H-NMR (CDCl₃, δ): 0.01 (s, 6H, CH₃ Si), 0.86 (s, 9H, Me₃ Si), 1.02 (d,J=5.75 Hz, 3H, CH₃ -21), 1.21 (s, 6H, CH₃ -26,27), 3.34 (d, J=10.8 Hz,1H, CHHOTBS), 3.49 (d, J=11.01 Hz, 1H, CHHOTBS), 3.36 (s, 3H, OCH₃),4.70 (s, 2H, OCH₂ O).

¹³ C-NMR (CDCl₃ δ): 18.20, 19.19, 19.32, 20.25, 23.81, 25.79, 26.27,26.37, 27.53, 35.35, 35.80, 36.39, 40.54, 42.21, 53.39, 55.03, 56.89,60.21, 61.78, 76.27, 91.03, 211.22.

EM [70 eV, m/z (%)]: 439 (M⁺ -CH₃, 0.92), 392 (M⁺ --HOCH₂ OCH₃, 0.03),335 (100), 225 (37.19), 149 (8.65), 119 (8.86).

(d) Ketone (40) serves as a common intermediate for the synthesis ofboth vitamin D analogues (49), according to Scheme J, and (46). Thevinyl triflate (41) is prepared by treatment of cpd.(40) with LDA andtrapping of the resulting kinetic enolate with N-phenyltriflimide: LDA(1.6 equiv.), THF, -78° C., cpd.(15) in THF, PhNTf₂ (2 equiv.) in THF, 2h, -78° C. room temp. (slowly); yield 82% [plus 14% cpd.(40)]. ¹ H-NMR(CDCl₃, δ): 0.03 (s, 6H, CH₃ Si), 0.88 (s, 9H, Me₃ CSi), 1.04 (d, J=5.75Hz, 3H, CH₃ -21), 1.21 (s, 6H, CH₃ -26,27), 3.36 (s,3H, OCH₃), 3.49 (s,2H, CH₂ OTBS), 4.70 (s, 2H, OCH₂ O), 5.64 (dd, J=3.38, 6.75 Hz, 1H,H-9).

¹³ C-NMR (CDCl₃,δ): 18.13, 19.15, 20.25, 21.39, 23.99, 25.78, 26.29,26.41, 28.19, 30.44, 35.69, 36.27, 42.15, 49.21, 49.58, 54.96, 55.03,60.03, 76.30, 91.02, 117.22, 121.20, 149.23.

(e) Synthon (42) is obtained in 68% yield from the correspondingtertbutyldimethylsilyl-protected enyne by deprotection (n-Bu₄ NF, THF)and reprotection (MOMCl, i-Pr₂ NEt).

¹ H-NMR (CDCl₃,δ): 1.68-1.80 (m, 1H, C₂ HH), 2.00 (s, 3H, CH₃ -19),2.12-2.25 (m, 1H, CH₂ -4), 2.55-2.64 (m, 1H, C₂ HH), 3.10 (a, 1H, HCC),3.38 (s, 3H, CH₃ O), 3.44 (s, 3H, CH₃ O), 3.93-4.04 (m, 1H, H-3), 4.12(t, J=3.96 Hz, 1H, H-1).

¹³ C-NMR (CDCl₃,δ): 18.79, 34.67, 36.41, 55.70, 55.75, 69.09, 74.98,80.43, 83.17, 95.22, 96.16, 115.73, 141.33.

Palladium-catalyzed assembly of both synthons (41) and (42) affordsdienyne (43): DMF, Et₃ N (3 equiv.), cpd.(42) (1 equiv.), (Ph₃ P)₂ PdCl₂(0.04 equiv.), 70-75° C., 75 min; yield 74%.

¹ H-NMR (CDCl₃,δ): 0.03 (s, 6H, CH₃ Si), 0.89 (s, 9H, Me₃ CSi), 1.05 (d,J=5.75 Hz, 3H, CH₃ -21), 1.22 (s, 6H, CH₃ -26,27), 3.38, 3.38 (ss, 6H,OCH₃), 3.43 (s, 3H, OCH₃), 3.45 (s, 2H, CH₂ OTBS), 3.98 (m, 1H, H-3),4.11 (m, 1H, H-1), 4.70, 4.71 (ss, 2H, OCH₂ O), 4.72 (s, 2H, OCH₂ O),6.05 (d, J=3 Hz, 1H, H-9).

(f) Dienyne (43) is converted to the previtamin (44) by partialhydrogenation in the presence of Lindlar catalyst: Hexane, Lindlar cat.,quinoline, H₂, room temp., 15 min; yield 93%.

(g) The previtamin is thermally equilibrated to a mixture of vitamin(45) and previtamin (44): Isooctane, 100° C., 5 h, ratio(45):(44)=85:15; yield 97%.

¹ H-NMR (CDCl₃, δ): 0.01 (s, 6H, CH₃ Si), 0.86 (s, 9H, Me₃ CSi), 1.02(d, J=5.75 Hz, 3H, CH₃ -21), 1.21 (s, 6H, CH₃ -26,27), 3.29 (a, 2H, CH₂OTBS), 3.36-3.45 (m, 9H, 3CH₃ O), 4.06 (m, 1H, H-3), 4.28 (m, 1H, H-1),4.6 (AB, J=6.65 Hz, 2H, OCH₂ O), 4.70, 4.71 (2s, 4H, OCH₂ O), 5.05 (s,1H, H₁,), 5.28 (s, 1H, H,), 5.96, 6.35 (AB, J=10.70 Hz, 2H, H-6,7).

EM [70 eV, m/z (%)]: 678 (M⁺, 2.04), 618 (2.09), 439 (5.65), 395 (6.54),281 (7.05), 208 (9.37), 119 (23.61), 103 (44.81), 45 (100).

(h) This mixture is subsequently subjected to deprotection with AG50W-X4® cation-exchange resin in methanol, to provide, after HPLCseparation, the desired vitamin D analogue (46): AG 50W-X4, MeOH, roomtemp., 6 days in the dark; yield of prod.(46) 41%.

¹ H-NMR (CDCl₃, δ): 1.10 (d, J=6.35 Hz, 3H, CH₃ -21), 1.19 (s, 6H, CH₃-26,27), 3.41 (d, J=5.11 Hz, 2H, CH₂ OH), 4.14 (m, 1H, H-3), 4.37 (m,1H, H-1), 5.30 (s, 1H, H_(19E)), 6.09, 6.35 (AB, J=11.1 Hz, 2H, H-6,7).¹³ C-NMR (CDCl₃, δ): 19.94, 21.69, 23.05, 24.54, 28.54, 29.11, 29.28,30.02, 36.46, 37.18, 37.91, 43.75, 45.36, 46.26, 50.92, 56.81, 58.46,60.27, 67.40, 71.54, 71.68, 112.28, 119.20, 124.80, 136.13, 142.53,149.83.

EXAMPLE XIX

Reaction (40)→(49) as shown in Scheme J.

(a) The reaction steps described in this Example are indicated with thenumbers of the compounds as used in Scheme J.

Reaction of cpd.(40) with phosphine oxide anion (47) affords theprotected vitamin D compound (48): 3 equiv. cpd.(47), THF, -78° C.,cpd.(40) in THF, 1 h; -78°→room temp.; yield 87%.

¹ H-NMR (CDCl₃, δ): 0.01 (s, 6H, Me₂ Si), 0.71 (s, 6H, Me₂ Si), 0.86 (s,9H, Me₃ CSi), 0.88 (s, 9H, Me₃ CSi), 1.01 (d, J=6.3 Hz, 3H, CH₃ -21),1.21 (s, 6H, CH₃ -26,27), 3.34 (s, 2H, CH₂ OTBS), 3.36 (s, 3H, CH₃ 0),3.81 (m, 1H, H-3), 4.70 (s, 2H, OCH₂ O), 4.76 (s, 1H, H₁₉₂), 5.00 (s,1H, H_(19E)), 5.98, 6.14 (AB, J=11.2 Hz, 2H, H-6,7).

¹³ C-NMR (CDCl₃, δ): -5.29, -4.63, 0.93, 15.19, 18.11, 19.31, 20.31,22.20, 23.45, 25.82, 26.30, 26.43, 27.85, 28.93, 32.02, 32,64, 35.72,36.33, 36.47, 42.16, 46.81, 49.75, 55.01, 55.44, 57.10, 60.78, 65.80,70.60, 76.36, 91.01, 111.98, 118.15, 121.38, 136.56, 141.14, 145.66.

(b) Deprotection as described in Example XVIII [cpd.(45)→(46)] gives thedesired vitamin D analogue (49) in 35% yield.

EXAMPLE XX

Biological experiments in vitro

Vitamin D analogue (46), prepared as described in Example XVIII, isdissolved in ethanol in concentrations ranging from 10⁻¹³ to 10⁻⁷ M. Theaffinity towards the calf thymus intracellular vitamin D receptor (VDR)is determined in a biological assay. In this assay ³ H-calcitriol(1α,25-dihydroxycholecalciferol), which is specifically bound to theVDR, is replaced by the tested compound. The IC50 value, i.e. 50%replacement of ³ H-calcitriol, is determined to be 2.5×10⁻¹⁰ M. Thisindicates, that the tested compound has a high affinity to the VDR andconsequently is a promising biologically active substance.

EXAMPLE XXI

Preparation of 1-(1,1-ethylenedioxy)ethyl-hydrindanol-4 [compound (2)]

Reaction (1)→(2) of Scheme A.

(a) The starting compound (1), viz. 7-dehydroprogesterone-3,20-diketal,in a quantity of 100 g is suspended into 1760 ml methanol and 88 ml drypyridine. After cooling down to -75° C. under N₂ and while stirring,this suspension is flushed with ozone during 9.5 hr.

(b) The intermediate hydrindanone-4 is not isolated, but directlyreduced by adding 24.8 g NaBH₄ to the above reaction mixture andstirring overnight at -75° C. Then another portion of 12.4 g NaBH₄ isadded at 75° C. and the reaction mixture is allowed to warm up to -40°C. Stirring overnight at room temp. Another portion of 12.4 g NaBH₄ isadded and the reaction mixture is stirred without external cooling for1.5 hr. After evaporation at reduced pressure, the residue is taken upin a mixture of 400 ml saturated NaCl-solution, 200 ml water and 300 mldiethylether. The layers are separated and the aqueous layer isextracted twice with 200 ml diethylether. The combined ether layers arewashed twice with 100 ml NaCl-solution, dried and evaporated to dryness.The desired hydrindanol compound (2) is obtained as a slightly yellowoil in a yield of 75.1 g. The product is subjected to flashchromatography: silicagel/ethylacetate. The pure product (approx. 97%pure according to NMR) is obtained as a colourless oil. (88%; Rf: 0.43,25% EtOAc/hexane; colourless oil).

¹ H NMR (CDCl₃, δ) 4.05 (1H,m,H-8), 3.99-3.80(4H, m, OCH₂ CH₂ O), 2.02(1H, m, H-17), 1.26 (3 H, s, Me-21), 1.00 (3 H, a, Me-17).

(c) In an alternative manner, hydrindanol compound (2) is prepared fromstarting compound (1) by a permanganate oxidation to the corresponding7,8-diol compound, followed by an oxidation by lead tetra-acetate and areduction: Aqueous KMnO₄ solution is added to solution of startingcompound (1) in 96% ethanol at -20° C. Reaction time approx. 2 hrs.Further processing: filtration over filter aid and evaporation todryness. Pb(OAc)₄ is added in portions to the diol, dissolved in drydichloromethane, under N₂ at -10° C. Reaction time approx. 1 hr. Furtherprocessing: filtration over filter aid. Reduction by Red-Al® [sodium(bis-methoxyethoxyaluminiumhydride], dissolved in toluene. Reaction timeapprox. 0.5 hr at -5° C.→room temp. Preparation procedure: filtrationand chromatographical purification (silicagel: ethylacetate/petroleumether). The desired hydrindanol compound (2) is obtained in a highpurity (NMR).

EXAMPLE XXII: (17)→(55). as shown in Scheme K

The reaction steps described in this Example are indicated with thenumbers of the compounds as used in Scheme K.

(a) Reaction (17) (50): Compound (17), obtained according to Example X,is oxidized to compound (50) in a corresponding manner as described inExample XVIII (c) as follows:

Compound (17) (661 mg) is dissolved under argon in 40 ml dichloromethaneand cooled to 0° C. PDC (2.002 g) is added and the reaction mixture isstirred at this temp. for 30 min., followed by stirring at room temp.for 38 h. Concentration under dim. pressure and column chromatography(silicagel; 15% EtOAc/hexane) yields 613 mg (93%) of the desiredproduct.

¹ H-NMR (CD₂ Cl₂, δ): 0.93 (d, J=6.7 Hz, 3H, CH₃ -21), 1.15 (s, 6H, CH₃-26,27), 3.28 (5, 3H, OCH₃), 4.62 (s, 2H, OCH₂ O), 5.08 (m, 2H, CH₂ ═),5.51 (dd, J=9.6, 18.6 Hz, 1H, CH═).

¹³ C-NMR (CD₂ Cl₂, δ): 18.65, 19.42, 20.72, 23.87, 26.47, 26.53, 27.86,35.69, 36.13, 36.50, 40.87, 42.60, 55.15, 56.80, 58.15, 61.73, 76.41,91.36, 116.97, 136.63, 211.09.

(b) Reaction (50)→(51) is performed in a corresponding manner asdescribed in Example XVIII (d) as follows:

iPr₂ NH (0.834 ml, 3.998 mmoles) is added dropwise to 2.35 M (1.685 ml)nBuLi under argon at -80° C. After adding 4 ml dry THF, the solution isallowed to reach 0° C. and stirred at this temp. for 30 min. Aftercooling to -80° C., an equimolar quantity of PhNTf₂ in THF is added,after which the reaction mixture is quenched with a few drops of MeOHafter having reached room temp. Concentration at dim. pressure andcolumn chromatography (silicagel; 5-20% EtOAc/hexane) yields 104 mg(66%) of the desired product.

¹ H-NMR (CDCl₃, δ): 0.92 (d, J=5.95 Hz, 3H, CH₃ -21), 1.20 (s, 6H, CH₃-26,27), 3.36 (s, 3H, OCH₃), 4.70 (s, 2H, OCH₂ O), 5.19 (m,2H, CH₂ ═),5.49 (dd, J=3.36, 6.78 Hz, 1H, H-9), 5.67 (m, 1H, C₁₈ H═). ¹³ C-NMR(CDCl₃,δ): 18.09, 20.39, 21.03, 23.91, 26.26, 26.33, 28.19, 31.41,35.74, 36.04, 42.26, 49.90, 52.61, 55.03, 55.12, 76.28, 91.03, 116.01,116.75, 134.63, 149.41.

(c) Reaction (51)→(52) is performed in a corresponding manner asdescribed in Example XVIII (e) as follows:

The triflate (51) in an amount of 107 mg, 96 mg of the enyne, 6 mg ofPd(Ph₃ P)₂ Cl₂ as a catalyst and 0.065 ml TEA are dissolved into 2 mlDMF. The solution is stirred under argon at 70-75° C. for 1 h 15 min.The reaction mixture is concentrated under reduced pressure and theresidue is chromatographed (silicagel; 5-10% EtOAc/hexane), yielding 115mg (73%) of the desired dienyne (52).

¹ H-NMR (CDCl₃, δ): 0.03 (5, 6H, CH₃ Si), 0.89 (8, 9H, Me₃ CSi), 1.05(d, J=5.75 Hz, 3H, CH₃ -21), 1.22 (s, 6H, CH₃ -26,27), 3.38, 3.38 (ss,6H, OCH₃), 3.43 (s, 3H, OCH₃), 3.45 (s, 2H, CH₂ OTBS), 3.98 (m, 1H,H-3), 4.11 (m, 1H, H-1), 4.70, 4.71 (ss, 2H, OCH₂ O), 4.72 (s, 2H, OCH₂O), 6.05 (d, J=3 Hz, 1H, H-9).

(d) Reaction (52)→(53) is performed in a corresponding manner asdescribed in Example XVIII (f) as follows: The dienyne (52) (45 mg) isdissolved into 6 ml hexane. A solution of quinoline in hexane (0.115 ml;solution of 0.060 ml quinolein in 10 ml hexane) and 50 mg of Lindlarcatalyst are added. The reaction mixture is flushed with hydrogen,filtered over celite and concentrated. Purification by columnchromatography (silicagel; 5-10% EtOAc/hexane) yields 43 mg (96%) ofprevitamin compound (53).

(e) Reaction (53)→(54) is performed in a corresponding manner asdescribed in Example XVIII (g) as follows: The previtamin (53) (40 mg)is dissolved into 4 ml iso-octane and heated at 110° C. for 5 h underargon. Concentration under red. pressure and column chromatographyyields 38 mg (92%) of the desired vitamin D compound (54).

(f) Reaction (54)→(55) is performed in a corresponding manner asdescribed in Example XVIII (h) as follows:

The vitamin compound (54) in an amount of 40 mg, dissolved in 10 mlMeOH, is stirred with 2 g resin AG 50W-X4® for 18 h under argon andshielded from the light. After filtration, washing with EtOAc (4×10 ml)and concentration under red. pressure, the product obtained ischromatographed: silicagel; 50% EtOAc/hexane, EtOAc. The desired18-vinyl modified 1α,25-dihydroxyvitamin D₃ (55) is obtained in a yieldof 13 mg.

¹ H-NMR (CD₂ Cl₂, δ): 0.88 (d, J=5.96 Hz, 3H, CH₃ -21), 1.13 (s, 6H, CH₃-26,27), 4.09 (m, 1H, H-3), 4.35 (m, 1H, H-1), 4.93 (s, 1H, H-19E), 5.06(ABX, J=11.3, 17.8 Hz, 2H, C₂ ═), 5.27 (s, 1H, H-19Z), 5.43 (ABX,J=11.4, 17.8 Hz, 1H, CH═), 6.02, 6.28 (AB, J=11.26 Hz, 2H, H-6,7). ¹³C-NMR (CD₂ Cl₂,δ): 18.45, 21.16, 22.15, 23.88, 27.87, 29.38, 29.51,36.26, 36.58, 37.02, 43.46, 44.89, 45.79, 56.82, 57.98, 67.16, 71.14,71.23, 111.90, 115.73, 116.79, 124.96, 134.28, 137.63, 142.93, 148.62.

EXAMPLE XXIII; (17)--(58), as shown in Scheme K

(a) Reaction (17)→(56):

Compound (17), obtained according to Example X, in an amount of 124 mgis dissolved into 10 ml of dry EtOH. In the presence of 40 mg 5% Pt/C asa catalyst the hydrogenation at a hydrogen pressure of 35 psi is carriedout at room temp. while stirring for 21 h. The solution is filtered overcelite, concentrated under dim. pressure and chromatographed (silicagel;15% EtOAc/hexane), to yield 121 mg (97%) of the desired product (56). ¹H-NMR (CDCl₃,δ): 0.91 (t, J=7.6 Hz, 3H, CH₃ -18), 0.98 (d, J=6.7 Hz, 3H,CH₃ -21), 1.22 (s, 6H, CH₃ -26,27), 3.37 (s, 3H, OCH₃), 4.10 (s, 1H,H-8), 4.71 (s, 2H, OCH₂ O).

¹³ C-NMR (CDCl₃,δ): 10.14, 17.57, 19.02, 19.52, 20.34, 22.04, 26.27,26.34, 26.83, 33.78, 34.82, 36.47, 36.71, 42.31, 44.48, 53.62, 55.00,58.45, 69.62, 76.35, 91.01.

(b) Reaction (56)→(57) is performed in a corresponding manner asdescribed in Example XXII (a).

¹ H-NMR: (CD₂ Cl₂, δ): 0.87 (m, 3H, CH₃ -18), 1.01 (d, J=6.19 Hz, 3H,CH₃ -21), 1.16 (s, 6H, CH₃ -26,27), 3.29 (s, 3H, OCH₃), 4.63 (s, 2H,OCH₂ O).

(c) Reaction sequence (57)→(58) is carried out in a corresponding manneras described in Examples XXII (b) to XXII (f).

Physical data:

triflate, compound (51)-analogue, wherein R₃ =ethyl:

¹ H-NMR (CDCl₃, δ): 0.97 (m, 3H, CH₃ -18), 1.01 (d, J=6.19 Hz, 3 H, CH₃-21), 1.21 (s, 6H, CH₃ -26,27), 3.37 (s, 3H, OCR₃), 4.71 (8, 2H, OCH₂O), 5.61 (dd, J=3.29, 6.57 Hz, 1H, H-9).

¹³ C-NMR (CDCl₃, δ): 10.19, 18.68, 19.33, 20.29, 20.68, 24.16, 26.32,27.68, 31.34, 35.23, 36.39, 42.30, 47.51, 51.44, 55.03, 56.38, 76.27,91.04, 116.45, 150.02.

coupling product, compound (52)-analogue, wherein R₃ - ethyl:

¹ H-NMR (CD₂ Cl₂, δ): 0.03 (s, 6H, Me₂ Si), 0.07 (s, 6H, Me₂ Si), 0.85(s, 9H, Me₃ CSi), 0.87 (s, 9H, Me₃ CSi), 0.93 (t, J=7.23 Hz, 3H, CH₃-18), 0.99 (d, J=6.38 Hz, 3H, CH₃ -21), 1.15 (s, 6H, CH₃ -26,27), 3.28(s, 3H, OCH₃), 4.06 (m, 1H, H-1), 4.62 (s, 2H, OCH₂ O), 5.95 (m, 1H,H-9). ¹³ C-NMR (CD₂ Cl₂, δ): -4.71, -4.59, -4.54, -4.25, 10.74, 18.28,18.36, 18.84, 19.27, 19.66, 20.75, 24.00, 25.87, 25.99, 26.04, 26.53,27.82, 32.94, 35.91, 36.96, 40.26, 41.66, 42.73, 44.68, 51.89, 55.15,57.22, 64.74, 70.44, 76.47, 88.54, 91.40, 93.01, 115.98, 123.22, 134,26,140.88.

vitamin D₃ derivative, compound (55)-analogue, wherein R₃ =ethyl:

¹ H-NMR (CD₂ Cl₂, δ): 0.81 (t, J=7.29 Hz, 3H, CH₃ -18), 0.98 (d, J=6.14Hz, 3H, CH₃ -21), 1.14 (s, 6H, CH₃ -26,27), 4.12 (m, 1H, H-3), 4.12 (m,1H, H-1), 4.92 (s, 1H, H-19E), 5.26 (s, 1H, H-19Z), 5.98, 6.33 (AB,J=11.26 Hz, 2H, H-6,7).

¹³ C-NMR (CD₂ Cl₂, δ) 9.52, 15.48, 18.52, 19.86, 21.10, 21.96, 24.21,27.38, 29.43, 29.56, 35.67, 36.78, 36.97, 43.50, 44.97, 45.87, 48.29,58.00, 58.82, 67.21, 71.17, 71.29, 111.92, 118.15, 125.05, 134.07,143.80, 148.63.

EXAMPLE XXIV

Reaction sequence (7)→(13) as shown in Scheme A "alt."

(a) The alternative ("alt.") oxidation of (7)→(9) is performed asfollows:

A stirred suspension of Pb(OAc)₄ (43.6 g) and CaCO₃ (8.27 g) in drycyclohexane (350 ml) is heated to 80° C. The starting compound (7) (5.00g) and iodine (6.50 g) are successively added, after which the reactionmixture is heated and irradiated with a 300 watt tungsten lamp for 3 h.

After cooling to room temp., the reaction mixture is filtered and washedwith Et₂ O. The filtrate is washed with 5% Na₂ S₂ O₃ solution and water.A drop of pyridine is added to the organic layer after separationthereof. Drying and concentration gives a residue which is dissolved inacetone. The solution is cooled to 0° C. and 10 ml of Jones reagent(13.3 g CrO and 11.5 ml conc. H₂ SO₄ diluted with water to 50 ml) isadded dropwise; the reaction mixture is stirred overnight. A solution ofNaOAc (100 g) and water (200 ml) is added and the mixture is filtered.The aqueous phase is extracted with EtOAc, and the combined organiclayers are washed with brine, dried, filtered and concentrated. Flashchromatography (5-10% EtOAc/hexane) yields 3.8 g (72%) of compound (9).

¹ H-NMRδ: 1.18 (d, J=6.7 Hz, 3H, CH₃ -21), 2.06 (s, 3H, OCOCH₃), 3.89(dd, J=6.3, 10.8 Hz, 1H, H-22), 4.07 (dd, J=3.5, 10.8 Hz, 1H, H-22), 4.6(d, J=4.7 Hz, 1H, H-8).

(b) Reaction sequence (9)→(13) of Scheme A "alt.".

(b-i): conversion of the acetate group into a hydroxy group. A solutionof compound (9) in methanol is stirred at room temp. in the presence ofK₂ CO₃ for 45 min. Addition of water, extraction with Et₂ O andworking-up procedure yields the corresponding hydroxy compound, afterflash chromatography, in a yield of 95%. ¹ H-NMR δ: 1.19 (d, J=6.7 Hz,3H, CH₃ -21), 3.48 (m, 1H, H-22), 3.65 (m, 1H, H-22), 4.58 (d, J=4.6 Hz,1H, H-8).

(b-ii): conversion of the hydroxy group into a iodo substituent.

The above hydroxy compound is treated with iodine in the presence ofPPh₃ and imidazole in dry THF at -7° C. for 15 min. Evaporation,addition of NaHCO₃, extraction with Et₂ O and working-up gives thedesired iodo compound after flash chromatography (5-10% EtOAc/hexane) ina yield of 96%. ¹ H-NMR δ: 1.15 (d, J=6.2 Hz, 3H, CH₃ -21), 3.32 (m, 2H,H-22), 4.58 (d, J=4.7 Hz, 1H, H-8).

(b-iii): conversion with methyl vinyl ketone.

The obtained iodo compound is treated with methyl vinyl ketone undersonication in deoxygenated EtOH/H₂ O in the presence of Zn dust and CuI:30 min. at room temp. under argon. Addition of Et₂ O and filtration. Thefiltrate is worked up and submitted to flash chromatography (5-10%EtOAc/hexane), yielding 88% of the desired 25-oxo-27-nor-lactonecompound. ¹ H-NMR δ: 1.09 (d, J=6.6 Hz, 3H, CH₃ -21), 1.57 or 2.13 (s,3H, CH₃ -26), 4.56 (d, J=4.5 Hz, 1H, H-8).

(b-iv): conversion to compound (13).

The above-obtained compound is treated with MeLi in dry Eto at -4° C.for 5 min. Quenching with water, and working-up of the organic phasegives a product, which after flash chromatography (10-20% EtOAc/hexane)yields compound (13) in a yield of 87%. ¹ H-NMR δ: 1.10 (d, J=6.6 Hz,3H, CH₃ -21), 1.21 (s, 6H, CH₃ -26,27), 4.55 (d, J=4.5 Hz, 1H, H-8).

(b-v): protection of the 25-hydroxy group.

The 25-hydroxy group can be protected by a reaction of theabove-obtained compound with chlorotriethylsilane in the presence oftriethylamine and 4-dimethylaminopyridine in dry CH₂ Cl₂ at 0° C.: 1 h,followed by stirring at room temp for 20 h. Addition of water,extraction with CH₂ Cl₂ and usual working up gives the trimethylsilylether of compound (13) in a yield of 87%. ¹ H-NMR δ: 0.54 [q, J=7.8 Hz,6H, Si(CH₂ Me)₃ ], 0.93 [t, 9H, J=7.8 Hz, Si(CCH₃)₃ ], 1.08 (d, 3H,J=6.5 Hz, CH₃ -21), 1.17 (s, 6H, CH₃ -26,27), 4.55 (d, 1H, J=4.5 Hz,H-8).

EXAMPLE XXV

Reaction sequence (9)→(70) as shown in Scheme L.

The reaction steps described in this Example are indicated again withthe numbers of the compounds as used in the Scheme.

(a) Reaction (9)→(59): Compound (9), obtained as described in ExampleXIII, is converted to compound (59) in a corresponding manner asdescribed in Example XXIV (b).

(b) Reaction (59)→(60):

Imidazole (95 mmoles) and t.-butyldimethylsilyl chloride (83.5 mmoles)are added to a stirred solution of 17.03 g of compound (59) in 200 mlDMF. After 20 hrs reaction at room temp., the reaction mixture isevaporated, and water and EtOAc/hexane are added. After separation, theorganic layer is washed with 0.2 N HCl solution, 5% NaHCO₃ solution andsatd. NaCl solution, dried and filtered. Concentration yields thedesired product (25.86 g). Purification by crystallization fromMeOH/EtOAc yields a crystalline material: m.p. 48-49° C.

¹ H-NMR (CDCl₃,δ): 0.86 [s, 9H, SiC(CH₃)₃ ], 1.12 (d, 3H, CH₃ -21), 2.31(m, 1H, CH-14), 3.43 (dd, 1H, CH-22), 3.52 (dd, 1H, CH-22), 4.54 (d, 1H,CH-8).

(c) Reaction (60)→(61) is performed in a corresponding manner asdescribed in Example XVIII (a). (d) Reaction (61)→(62) is performed in acorresponding manner as described in Example X. ¹ H-NMR (CDCl₃,δ): 0.86[s, 9H, SiC(CH₃)₃ ], 0.88 (d, 3H, CH₃ -21), 2.51 (m, 1H, CH-14), 3.28(dd, 1H, CH-22), 3.49 (dd, 1H, CH-22), 3.93 (b, 1H, CH-8), 5.26 (m, 2H,═CH₂), 5.88 (m, 1H, --CH═C).

(e) Reaction (62)→(63):

An aqueous HF solution (94 mmoles) is added dropwise to a stirredsolution of 17.61 g of compound (62) in acetonitrile. After 20 min atroom temp. a 5% NaHCO₃ solution is added and the reaction mixture isstirred for an additional 10 min. The reaction mixture is poured into asatd. NaCl solution and extracted with diethylether (3x). After washingwith satd. NaCl solution, the organic phase is dried, filtered andconcentrated under red. pressure, yielding the desired compound (12.04g). ¹ H-NMR (CDCl₃,δ): 0.96 (d, 3H, CH₃ -21), 2.53 (dt, 1H, CH-14), 3.39(dd, 1H, CH-22), 3.58 (d, 1H, CH-22), 3.96 (b, 1H, CH-8), 5.29 (m, 2H,═CH₂), 5.99 (m, 1H, CH═C).

(f) Reaction (63)→(64):

Pd/C 10% (500 mg) as a catalyst is added to a solution of 11.60 g ofcompound (63) in MeOH. The reaction mixture is hydrogenated in a Parrapparatus for 17 hours (pressure approx. 3.5 bar). The reaction mixtureis filtered over celite, concentrated under red. pressure andchromatographed over silicagel (petr.ether/EtOAc--55/45), yielding 11.4g of compound (64). ¹ H-NMR (CDCl₃, δ): 0.92 (t, 3H, CH₃ -18), 1.11 (d,3H, CH₃ -21), 2.31 (dt, 1H, CH-14), 3.40 (m, 1H, CH-22), 3.65 (m, 1H,CH-22), 4.11 (b, 1H, CH-8).

(g) Reaction (64)→(18A) is performed in a corresponding manner asdescribed in Example XXIV (b). ¹ H-NMR (CDCl₃, δ): 0.91 (t, 3H, CH₃-18), 1.08 (d, 3H, CH₃ -21), 2.26 (m, 1H, CH-14), 3.23 (dd, 1H, CH-22),3.33 (dd, 1H, CH-22), 4.12 (b, 1H, CH-8).

(h) Reaction (18A)→(65) is performed in a corresponding manner asdescribed in Example XVIII (c). ¹ H-NMR (CDCl₃, δ): 0.89 (t, 3H, CH₃-18), 1.13 (d, 3H, CH₃ -21), 2.49 (m, 1H, CH-14), 3.23 (dd, 1H, CH-22),3.32 (dd, 1H, CH-22).

(i) Reaction (65)→(66) is performed in a corresponding manner asdescribed in Example XVIII (d).¹ H-NMR (CDCl₃,δ): 0.97 (t, 3H, CH₃ -18),1.11 (d, 3H, CH₃ -21), 2.58 (m, 1H, CH-14), 3.21 (dd, 1H, CH-22), 3.32(dd, 1H, CH-22), 5.63 (q, 1H, CH-9).

(j) Reaction (66)→(67) is performed in a corresponding manner asdescribed in Example III. ¹ H-NMR (CDCl₃, δ): 0.96 (t, 3H, CH₃ -18),1.02 (d, 3H, CH₃ -21), 1.26 (t, 3H, OCCH₃), 2.51 (m, 1H, CH-14), 4.13(q, 2H, OCH₂ C), 5.61 (q, 1H, CH-9).

(k) Reaction (67)→(68) is performed in a corresponding manner asdescribed in Example XXII (c) ¹ H-NMR (CDCl₃, δ): 0.06 (s, 6H, SiMe₂),0.09 (s, 6H, SiMe₂), 0.88 [2xs, 2×9H, 2xSiC(CH₃)₃ ], 0.94 (t, 3H, CH₃-18), 1.02 (d, 3H, CH₃ -21), 1.26 (t, 3H, OCCH₃), 1.89 (b, 3H, CH₃ -19),2.40 (m, 1H, CH-14), 4.09 (b, 1H, CH-3), 4.13 (q, 2H, OCH₂ C), 4.19 (b,1H, CH-1), 6.01 (b, 1H, CH-9).

(1) Reaction (68)→(69) is performed in a corresponding manner asdescribed in Example XXII (d).

(m) Reaction (69)→(70) is performed in a corresponding manner asdescribed in Example XXII (e). ¹ H-NMR (CDCl₃, δ): 0.06 (s, 6H, SiMe₂),0.09 (s, 6H, SiMe₂), 0.88 [s, 18H, 2×SiC(CH₃)₃ ], 0.89 (t, 3H, CH₃ -18),1.01 (d, 3H, CH₃ -21), 1.26 (t, 3H, OCCH₃), 2.45 (m, 1H, CH-14), 4.13(q, 2H, OCH₂ C), 4.37 (m, 1H, CH-1), 4.19 (m, 1H, CH-3), 4.86 (b, 1H,CH-19Z), 5.17 (b, 1H, CH-19E), 6.01 (d, 1H, CH-7), 6.24 (d, 1H, CH-6).

(n) Reaction (70)→(58) is performed by subjecting compound (70) to aconventional double Grignard reaction (MeMgX) or to a reaction withMeLi, followed by deprotection in a corresponding manner as described inExample XXII (f). So the desired C-18 modified 1α,25-dihydroxyvitamin D₃compound (58) is obtained.

EXAMPLE XXVI

Reaction sequence (71)→(74) as shown in Scheme N.

The reaction steps described in this Example are again indicated withthe numbers of the compounds as used in the Scheme.

(a) Reaction (71)→(72):

Compound (71), prepared from vitamin D₃ in a corresponding manner asdescribed in Example I, is converted to compound (72) in a correspondingmanner as described in Example IV. ¹ H-NMR (CDCl₃,δ): 0.86 (dd, 6H,CH-26,27), 0.88 (d, 3H, CH₃ -21), 2.06 (dd, 1H, CH-14), 3.72 (m, 2H,OCH₂ -C18), 4.14 (d, 1H, CH-8).

(b) Reaction (72)→(13):

RuO₂.xH₂ O (0.01 mol) and NaIO₄ (0.606 mol) are stirred in water. Tothis mixture is added 26.62 g of compound (72), dissolved in EtOAc. Thereaction mixture is stirred vigorously at 60° C. for 3 h 45 min. Thendiethylether and satd. NaCl solution are added and the reaction mixtureis filtered over celite. After separation, the organic phase is washedwith water and satd. NaCl solution, dried, filtered and concentratedunder red. pressure. Purification by column chromatography (silicagel;petr.ether/EtOAc--93/7 70/30) yields 10.0 g of compound (13), inaddition to intermediate (73) (9.0 g).

Compd. (73): ¹ H-NMR (CDCl₃, δ): 0.86 (dd, 6H, CH₃ -26,27), 1.09 (d,3H,CH₃ -21), 2.36 (m, 1H, CH-14), 4.55 (d, 1H, CH-8).

Compd. (13): ¹ H-NMR (CDCl₃, δ): 1.09 (d, 3H, CH₃ -21), 1.20 (d, CH₃-26,27), 2.35 (m, 1H, CH-14), 4.56 (d, 1H, CH-8).

(c) Reaction (13)→(74): Lutidine (2.6 g, 63.4 mmoles) andtriethylsilyltriflate (39.6 mmoles) are added to a solution of 9.35 g ofthe above compound (13) in dry dichloromethane. After 30 min water isadded. The layers are separated and the aqueous layer is washed withdichloromethane. The collected organic layers are dried, filtered andconcentrated under red. pressure. The residue is purified by columnchromatography (silicagel; petr.ether/EtoAc=95/5), yielding 13.16 g ofcompound (74).

¹ H-NMR (CDCl₃, δ): 0.58 (q, 6H, 3×SiCH₂ CH₂), 0.94 (m, 9H, 3×SiCCH₃),1.09 (d, 3H, CH₃ -21), 1.18 (d, 6H, CH₃ -26,27), 2.37 (m, 1H, CH-14),4.55 (d, 1H, CH-8).

We claim:
 1. A vitamin D compound of the general formula ##STR19##wherein R₁ is a hydrogen atom or a hydroxy group;R₃ is a C₂ -C₅ alkylgroup, R₄ is a hydrogen atom or a C₁ -C₄ alkyl group; R₅ is a branchedor non-branched, saturated or unsaturated aliphatic hydrocarbyl orhydrocarbyloxy group, which comprises 1 to 16 carbon atoms and which isoptionally substituted with one or more substituents, selected fromhydroxy groups, ether groups, oxo functions, cyclopropyl groups, lactonegroups and fluorine atoms; R is a hydrogen atom or a C₁ -C₄ alkyl group;and A and B are each individually hydrogen atoms or methyl groups, or, Aand B form together a methylene group.
 2. A method of preparing avitamin D compound as claimed in claim 1, characterized in that ahydrindane compound of the general formula X: ##STR20## wherein R₈ is ahydroxy-protecting group; is converted to the corresponding cyanohydrinof the general formula XI ##STR21## wherein R₈ has the above meaning;after which said cyanohydrin is converted to a hydrindane intermediateof the general formula XII ##STR22## which intermediate is subjected toa reaction sequence to produce, in a manner known per se for relatedcompounds, substitutent R₃ in the 7a position and to convert substituentCH₃ O into substituent R₄ C(R₅)R₆ ; after which the hydrindane compoundobtained, having the general formula IX ##STR23## wherein R₃, R₄, R₅ andR₆ are as defined in claim 1, is converted in a manner known per se forrelated compounds, either (a) with a Wittig reagent of the generalformula V ##STR24## wherein: R₁ is a hydrogen atom or a protectedhydroxy group,R₂ is a protected hydroxy group, and A and B have themeanings given in claim 1, or (b), after enolization, with an enynecompound of the general formula VI ##STR25## where R₁ and R₂ have theabove meanings, followed by hydrogenation and equilibration; into avitamin D compound of the general formula I ##STR26## wherein thesubstituents R₁, R₃, R₄, R₅, R₆, A, and B are as defined in claim
 1. 3.A vitamin D compound as claimed in claim 1, wherein R₁, R₃, A and B havethe meanings given in claim 1,R₄ is a methyl group, R₆ is a hydrogenatom or a methyl group, and R₅ is an aliphatic hydrocarbyl groupselected from the group consisting of 3,4-dimethylpenten-1-yl,3,4-dimethyl-4-hydroxpenten-1-yl, 3-hydroxy-4-methylpentyl,4-hydroxy-4-methylpentyl, 3,4-dihydroxy4-methylpentyl,3,3-difluoro-4-hydroxy-4-methylpentyl, 3-methylbutoxy,3-hydroxy-3-methylbutoxy, 3-cyclopropyl-3-hydroxypropen-1-yl and3-cyclopropyl-3-hydroxy-3-3-3-methylpropen-1-yl; or its corresponding24-homo-, 26-homo-24,24-dihomo-26,27-dihomo-24,26,27-trihomo- or24,26,27-tetrahomo-vitamin D analogue.